Lecture #16-19 Interventional Studies Flashcards
What are other terms used to explain interventional study designs
Clinical trial, clinical study, experimental study, human study, investigational study
What is the key difference between observational and interventional studies
Investigator selects “interventions” and allocates study subjects to forced-intervention groups in interventional studies
Which type of study observational or interventional is able to demonstrate causation
Interventional. It is more “rigorous” in ability to show a cause- and-effect
What does Pre-Clinical mean
It is a phase of interventional studies.
of all the phases it has the lowest strength of evidence
it is prior to human investigation
bench and animal research
what is phase 1
It is a phase of interventional studies it is after the pre-clinical phase small N (about 20-80), healthy volunteers (can also be sick) are used for the first time in humans to assess safety/toxicity, dosing and even pharmacokinetics in population of interest (diseased) - short duration (e.g. usually just a few days or weeks or couple of months)
How long does phase 1 of interventional studies last
short duration
usually a few days or weeks or couple of months
What is the typical sample size for phase 1 of interventional studies
small about 20-80
Explain phase 2 trials
larger N (about 100-300 people) commonly utilize patients with condition of interest, used to expand on purpose of Phase 1 study (safety) but also to begin assessing efficacy in diseased population short-to-medium duration (few to several months) Likely to have a narrower inclusion criteria
What is the sample size in phase 2 trials
about 100-300 patients
What is the duration of Phase 2 trials
shot to medium duration (a few to several months)
who is the typical study sample for phase 2 trials
about 100-300 patients,
commonly utilize patients with condition of interest
what is the purpose of phase 2 trials
used to expand on purpose of phase 1 study (safety) but also to begin assessing efficacy in diseased population
who is used in phase 1 trials
healthy volunteers (can use sick volunteers, this is usually done in cancer research)
What is the purpose of phase 1 trials
to assess safety/toxicity, dosing and even pharmacokinetics in population of interest (diseased)
Explain a Phase 3 trial
after phase 2
larger N (about 1,000-3,000) used in patients with condition of interest to continue determination of safety, with primary purpose to assess efficacy
- Longer duration (many months to a year (or few years)
- Superiority vs. Non-Inferiority vs. equivalency formats
what is the sample size for phase 3 trials
about 1,000-3,000 patients with conditions of interest
What is the purpose of phase 3 trials
To continue determination of safety, with primary purpose to assess efficacy
What is the duration of a phase 3 trial
many months to a year (or a few years)
What kind of patients are used for phase 3 trials
Patients with the condition of interest
what is a phase 4 study
Post-marketing
Long -term effects (risk and benefits) in a large population of diseased patients (expanded use population (age, ethnic))
Phase 4 studies utilize what
Registries, Surveys’s (ex. FDA’s MedWatch/FAERS/VAERS programs)
what is the purpose of a phase 4 study
Long-term effects (risk and benefits) in a large population of diseased patients
who is used in phase 4 studies
large population of diseased patients
What are some advantages of interventional trials vs. other designs
Cause precedes effect (shows causation)
only design used by FDA for “approval” process (on-label)
What are some disadvantages of interventional trials vs. other designs
Cost, Complexity/time (development/approval/conductance)
Ethical considerations (risk vs. benefit evaluation)
Generalizability (a.k.a External Validity)
What are 4 types of designs of interventional studies
Simple, Factorial,Parallel, Cross-over (a.k.a. Self-control)
Explain a simple interventional study
Divides (randomizes) subjects exclusively into greater than or equal to 2 groups
- a single randomization process; no subsequent randomized divisions
Commonly used to test a single hypothesis (question) at a time.
When is a simple interventional study commonly used
to test a single hypothesis (question) at a time
How many groups does a simple interventional study divide (randomize) subjects into
Greater than or equal to 2 groups
Explain a factorial interventional study
Divides subjects into greater than or equal to 2 groups and then further additionally sub-divides (randomizes) each of the groups into greater than or equal to 2 sub-groups
- numerical representation of numbers of groups and number of divisions ( 2x2 or 3x3x2) * * used to test multiple hypotheses at the same time (increases sample size requirement)
Why is a factorial interventional study design used
to test multiple hypotheses at the same time (increases sample size requirement)
what some characteristics of factorial interventional study designs
improves efficiency for answering clinical questions
increases study population sample size (due to increased group #)
increases complexity (which may be a barrier to recruitment)
Increases risk of drop outs (due to complexity)
may restrict generalizablility of results
What are some weaknesses of factorial interventional study designs
increases study population sample size (due to increased group #)
increases complexity (which may be a barrier to recruitment)
Increases risk of drop outs (due to complexity)
may restrict generalizablility of results
What are some strengths of factorial interventional study designs
Improves efficiency for answering clinical questions, used to test multiple hypotheses at the same time
Explain Parallel interventional study designs
Groups simultaneously and exclusively managed
No switching of intervention groups after initial randomization
- all simple and factorial study designs are also parallel
All simple and factorial study designs are also what
Parallel study designs
Explain Cross-Over (aka Self-Control)
Groups serve as their own control by crossing over form one intervention to another during the study
- allow for a smaller total "N" (sample size)
- each patient contributes additional data
What is the Run-In/ Lead-In phase
a way to assess placebo-effects, Hawthorne-effects and compliance BEFORE a study begins
- all study subjects blindly given one or more placebos for initial therapy (defined time-period) to determine a “new” base-line of disease (standardization)
- can assess study protocol compliance
- Can “ wash-out” existing medications
- Reduces at least 1 possible common exclusion criteria- can determine amount of placebo-effect (new baseline
what are 6 disadvantages of Cross-Over interventional study designs
- only suitable for long-term conditions which are not curable or which treatment provides short-term relief
- duration of study for each subject is longer
- carry-over effects during cross-over (wash-out required; which prolongs study duration)
- Treatment-by-Period interaction
- Differences in effects of treatments during different time periods - Smaller N requirement only applicable if within-subjects variation less than between-subjects variation
- complexity in data analysis
What are the phases of interventional study designs that are largely concerned with safety.
Phase 1 and 4
Which phases of interventional study design are mostly concerned with efficacy and effectiveness
Phase 2 and 3
Will you ever see a drug without a name in a phase 4 trial
No!
Is safety a concern in all phases of a study
Yes but may not be the main focus in phases 2 and 3
Dummy in terms of epidemiology means what
placebo
Equipoise
Genuine confidence that an intervention may be worthwhile (risk vs. Benefit) in order to use it in humans
What are some advantages of interventional trials vs. other designs
cause precedes effect (shows causation)
only design used by FDA for “approval” process (on-label)
what are some disadvantages of interventional trials vs. other designs
- Cost
- complexity/Time (development/approval/conductance) because they are prospective in nature
- Ethical considerations (risk vs. benefit evaluation)
- Generalizability (a.k.a; External validity)
What is usually the number one reason why observational studies are better
Ethics
What is the difference between explanatory and pragmatic studies
explanatory has a rule to play by and can’t manipulate it per patient
pragmatic trials allow you to use clinical practices to manipulate the studies
pragmatic trials never really use placebos
Pragmatic let regular people in
What does it mean that pragmatic trials let regular people in
The allow people with multiple comorbidities and on multiple medications
What is a weakness of pragmatic studies
loss of control and may have multiple cofounders present
The fluid mosaic model describe the overal organization of a biological membranes. The essence of their model is that memrbanes are _______ dimensional solutions of______ and ______
Two, oriented lipids, globular proteins
what is the lipid bilayers dual roles
it is a solvent for integral membrane proteins and a permeability barrier
what does within group and between group during cross-over study mean
Between groups is the normal comparision between A and B. In group refers to the ability to see how an individual performs when they are in both groups (self-control)
What are the disadvantages of Cross-Over design
- only suitable for long-term conditions which are not curable or which treatment provides short-term relief
- Duration of effects during cross-over (wash-out required; which prolongs study duration)
- Treatment-by-Period interaction
- Differences in effects of treatments during different time periods
- Smaller N requirement only applicable if within subjects variation less than between subjects variation
- complexity in data analysis
Examples of Patient-Oriented Endpoints (most clinically relevant)
Death, Stroke or MI, Hospitalization, preventing need for dialysis
Examples of surrogate Markers (elements used in place of evaluating patient-oriented (direct) endpoints
Blood pressure (for risk of stroke), Cholesterol (for risk of heart attack), Change in SCr (for worsening renal function)
What are convenience sampling/non-probabilistic allocation
Non-random sampling
What is the major purpose of Randomization
To remove bias and make groups as equal as possibel
is equality of groups guaranteed when using randomization
No
What is Table 1
It shows you how the randomization shook out and the statistics to show the groups equality
_______ attempts to reduce systematic differences (bias) between groups which could impact results/outcomes
Randomization
What are 3 examples of forms of randomization
simple, blocked, stratified
What is simple randomization
equal probability for allocation within one of the study groups
What is blocked randomization
ensures balance within each intervention group
- used when researcher wants all groups to have equal size
What is stratified randomization
ensures balance with known confounding variables
- examples: gender, age, disease severity/ duration, comorbidites
can also pre-select levels to be balanced within each interfering factor (confounder)
What are three kinds of masking
single-blind, doube-blind, open-label
What is a single-blind study
Study subjects are not informed which intervention they are receiving (but clinicians/researchers are)
What is a double blind study
Neither investigators nor study subjects are informed which intervention each subjects is receiving
What is a open-label study
Everyone knows which intervention each subject is receiving
What is a post-hoc’s survey
can be used to assess adequacy of blinding
When is a single-blind okay
When the researcher is not interacting with them and is unable to influence the results
What is a placebo (dummy) therapy
inert treatments made to look identical in all aspects to the active treatments
- dosage forms, dosing frequency, monitoring, therapy requirements, etc.
What is a double-dummy
more than 1 placebo used
What is the placebo effect
Improvement in condition; by power of suggestion and due to the care being provided
- can be as large as 30-50%
Hawthorne-effect
Desire of study subject to “please” investigators by reporting positive results (improvement), regardless of treatment allocation.
- desire for positive outcome to process
How large can the placebo effect be
30-50%
Post-hoc sub-group analysis is _______ as appropriate, by most, when not prospectively planned
Not accepted
What is post-hoc sub-group analysis called when it is retrospective
Data-dredging or fishing
Post-hoc sub-group analysis can do what the the power and increases the risk of what
Reduces power and increases risk of Type 2 error
In sample size determination they add in who
anticipated drop-out or loss to follow up rates
How can one manage drop-outs/Lost-to-follow-ups
Intent-to-treat and Per-protocol or Efficacy-Analysis, as-treated
What is the most conservative decision on how to manage drop-outs/lost-to-follow ups
Intent-to-Treat
Explain Intent-to-Treat
The most conservative way to manage drop-outs/lost-to-follow up
- last known assessment (observation) used for (carried forward) all subsequent, yet missed assessment (LOCF)
- Convert all subsequent yet missed assessments for a subjects to a null-effect (no-benefit)
-preserves randomization process
- Preserves baseline characteristics and group balance at
baseline which controls for known and unknown confounds
- Maintains statistical power (original sample size)
What is per-protocol or efficacy-analysis
compliance must be pre-defined
- customarily set at 80-90 % with study protocol
Wash-Out period
The longest period needed to reduce both groups to baseline
The post hoc analysis must be
Pre-defined and compliance must be greater than 80-90%
